Transferrin, the iron-transporting protein of blood plasma, consists of a single polypeptide chain bearing two specific and distinguishable iron-binding sites. We are studying the differences in the chemistry of metal-binding by each site, using spectroscopic, thermodynamic, and protein modification methods. A major interest is whether there are also differences between the sites as they function to exchange iron among tissues where the metal is absorbed, stored, excreted or utilized for the biosynthesis of essential iron enzymes and proteins (i.e., hemoglobin and myoglobin). We are exploring the interaction of transferrin with its specific tissue receptors, and are characterizing the molecular properties of these receptors. A major effort is the study of mechanisms underlying transferrin's function as an iron donor or acceptor for liver cells. In all of this work we hope to improve our understanding of transferrin functions in the regulation of iron metabolism, and to see the use made of this understanding in developing more effective therapies for disorders of iron metabolism.